The activity of immune checkpoint inhibitors in patients with recurrent cervical cancer developed in previously irradiated field: clinical and immunohistochemical investigations.

Objective: We aimed to 1) evaluate the efficacy of immune checkpoint inhibitors (ICIs) in cervical cancer patients according to the site of disease, 2) investigate the mechanism responsible for differential ICIs sensitivities with focuses on CD8⁺ T lymphocytes and programmed death-ligand 1 (PD-L1) expression.

Methods: We retrospectively reviewed clinical data from patients with recurrent or metastatic cervical cancer treated with pembrolizumab or cemiplimab between January 2019 and January 2024 (clinical cohort). Target diseases were classified according to the site of diseases: within previously irradiated field (in-field diseases), out-of-field diseases, and both. Immunohistochemical investigations were performed using paired tumor samples (i.e. initial cervical tumor and locally-recurrent tumor developed after definitive radiotherapy: Immunohistochemical cohort). Survival rates were estimated using the Kaplan-Meier method and compared using the log-rank test.

Results: Fifty patients treated with pembrolizumab-containing chemotherapies (n=39) or cemiplimab (n=11) were assessed. Of these, six patients (12.0%) had in-field diseases alone, twenty-eight patients (56.0%) had out-of-field diseases, and the remaining sixteen (32%) patients had both types of diseases. In-field diseases demonstrated a significantly lower response rate compared to out-of-field diseases (36.3% vs. 72.7%, p=0.004). Patients with in-field diseases demonstrated significantly shorter progression-free survival (p=0.003) and overall survival (p=0.003) than those with out-of-field diseases. In-field diseases were associated with decreased tumor-infiltrating CD8⁺ T lymphocytes and PD-L1 expression.

Conclusion: In-field cervical cancer recurrence was associated with decreased sensitivity to ICIs-containing chemotherapies when compared to out-of-field diseases. Decreased tumor-infiltrating CD8⁺ T lymphocytes and PD-L1 expression are possible reasons for this differential sensitivity to ICI-containing chemotherapies.